Osimertinib Resistance Mechanisms in EGFR T790M–Positive NSCLC

Key Points

Osimertinib resistance was accompanied by known EGFR TKI resistance mutations in some patients.

In some patients with loss of T790M, new resistance mechanisms were identified, including acquired KRAS mutations and targetable gene fusions.

In a study reported in JAMA Oncology, Oxnard et al found early resistance and a number of competing resistance mechanisms in acquired osimertinib (Tagrisso) resistance associated with loss of the T790M mutation conferring resistance to prior EGFR tyrosine kinase inhibitor (TKI) treatment in patients with non–small cell lung cancer (NSCLC).

Study Details

The study included 143 patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR TKIs from a multi-institutional cohort. Next-generation sequencing of tumor biopsies was performed in patients developing osimertinib resistance.

Resistance Mechanisms

Among the 143 patients evaluated, 41 patients (including 28 women, 68%) had tumor next-generation sequencing after acquired resistance to osimertinib. Among 13 patients (32%) with maintained T790M at the time of resistance, EGFR C797S was found in 9 (22%). Among 28 patients (68%) with loss of T790M, several competing resistance mechanisms were identified. Recognized resistance mechanisms after first-generation EGFR TKIs were found in 13 of these patients, including 6 cases of small cell lung cancer transformation, 4 MET amplifications, 2 PIK3CA mutations, and 2 BRAF mutations. Other patients with T790M loss had unexpected resistance mechanisms, including RET, FGFR3, and BRAF fusions and a KRAS Q61K mutation that occurred along with EGFR 19 deletion mutation.

Time to osimertinib discontinuation was shorter in patients with T790M loss (6.1 vs 15.2 months), indicating the potential emergence of preexisting resistant clones. A similar finding was made in a validation cohort of 110 patients who had plasma cell-free DNA genotyping after development of osimertinib resistance. The loss of T790M at development of osimertinib resistance was associated with a smaller decrease in levels of the EGFR driver mutation in serial plasma evaluations after 1 to 3 weeks of therapy (decrease of 100% vs 83%, P = .01).

The investigators concluded, “Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance.”

The study was supported by Damon Runyon Cancer Research Foundation, National Cancer Institute, AstraZeneca, and others.

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